The goal of the research proposed in this application is to elucidate the molecular mechanisms involved in the production of the cardiac contractile apparatus during normal development and hypertrophy. These studies will be focussed on the major contractile protein, myosin heavy chain (MHC). Using recombinant DNA techniques we will determine how many MHC genes are expressed in the heart, as well as, their specific induction and de-induction, at precise stages of pre- and post-natal development. The fine structure of the cardiac MHC genes will be analyzed and the complete nucleotide sequenceof one fetal and one adult cardiac mRNA will be determined. From these sequences the amino acid sequence of the corresponding MHCs will be deduced. In parallel, we will analyze the changes producedin the expression of MHC genes by different types of cardiac work overload that changes myocardial contractility and/or MHC isozyme pattern: hypo- and hyperthyroidism, diabetes, as well as systolic and diastolic mechanical overload. The molecular mechanisms (chromatin conformation of the MHC genes, rates of transcription and mRNA stability) responsible for the production of the MHC isozyme changes will be determined.